Most of the current drugs used to treat cancer can be classified as anti-proliferative drugs. These drugs perturb the proliferative cycle of tumor cells at diverse stages of the cell cycle. Examples of such drugs are DNA-damaging agents and inhibitors of cyclin-dependent kinases that arrest cell cycle progression at different stages of interphase. Another class of anti-proliferative drugs is the so-called anti-mitotic drugs, which selectively perturb progression through mitosis. Mitosis is the shortest and final stage in the cell cycle and has evolved to accurately divide the duplicated genome over the two daughter cells. This review deals with the different strategies that are currently considered to perturb mitotic progression in the treatment of cancer.
Need for the mitotic checkpoint
One way to kill mitotic cells is to increase the duration of mitosis by perturbing correct formation of the mitotic spindle that is needed for chromosome alignment and segregation. Two well established classes of anti-cancer drugs, which induce a severe delay in mitotic progression, are taxanes and vinca alkaloids (Manfredi and Horwitz, 1984; Jordan and Wilson, 2004). These drugs affect microtubule dynamics and cause abnormal spindle formation (Rowinsky et al., 1988; Jordan et al., 1991; Jordan et al., 1993). Perturbation of spindle assembly precludes proper alignment of the chromosomes and as a consequence the mitotic checkpoint or spindle assembly checkpoint maintains cells in mitosis, to provide the cell time to resolve these errors in alignment. This checkpoint comprises a large number of proteins, which together create a ‘wait-anaphase’ signal that delays mitotic progression (Kops, 2008). Thus, any drug that induces erroneous chromosome alignment will prevent silencing of the mitotic checkpoint and will result in an extensive mitotic arrest, eventually leading to cell death.
The two conventional microtubule-targeting drugs; the Vinca alkaloids and the taxanes, have been shown to be effective in the treatment of different types of cancer. One newly described family of microtubule-stabilizing drugs consists of Epothilones, which bind at the taxane-binding site on microtubules (reviewed in Goodin, 2008). This drug is currently being evaluated in clinical trials for the use in several types of cancer and might be useful in the treatment of paclitaxel-resistant tumors in the future (Jordan and Wilson, 2004; Yue et al., 2010).
Besides many clinical success stories, anti-microtubule targeting drugs have severe side effects, which are in part caused by general perturbation of cell proliferation, resulting in myelosuppression. However, the dose-limiting toxicities of these drugs are largely a consequence of the general disturbance of microtubule dynamics that they induce, causing serious neurotoxicity. In addition, acquisition of resistance is quite common in patients treated with anti-microtubule drugs (Rowinsky et al., 1993; Tuxen and Hansen, 1994; Jordan and Wilson, 2004). Thus, while the induction of a mitotic delay does seem to have a relatively specific cytotoxic effect on cancerous tissue, the side effects unrelated to the anti-mitotic effects of these drugs restrict their application. This has instigated a search for more mitosis-selective drugs. More specific details on the mechanism of action of the different families of microtubule-targeting drugs has been reviewed elsewhere (Jordan and Wilson, 2004; Harrison et al., 2009; Yue et al., 2010). In this review, we will focus more on recently identified mitotic targets and the possibility of exploiting these targets in anti-cancer treatment.
One of the targets that was proposed for a mitosis-selective approach is the plus end-directed motor protein Eg5 (kinesin-5). Eg5 has the capacity to drive centrosome separation in prophase, which initiates bipolar spindle assembly (Sawin et al., 1992; Blangy et al., 1995). Inhibition of Eg5 motor activity results in assembly of a monopolar spindle, causing a defect in chromosome congression and consequently chronic mitotic checkpoint activity (Blangy et al., 1995; Mayer et al., 1999; Kapoor et al., 2000) (Figure 1). Eg5 inhibition has been shown to effectively kill taxol-resistant cell lines (Marcus et al., 2005), making it an attractive anti-cancer target. Indeed, a variety of potent and selective Eg5 inhibitors have been generated over the last couple of years and some of them have entered clinical trials (Table 1). Although limited cytotoxicities have been found in patients treated with Eg5 inhibitors, only partial responses have been reported so far (Huszar et al., 2009). In addition, several reports have shown that mutations in Eg5 occur, which can confer resistance to these compounds (Brier et al., 2006; Maliga and Mitchison, 2006; Tcherniuk et al., 2010). On top of that, other motor proteins can act redundantly with Eg5 and increased expression of Kif15 allows cancer cells to overcome a mitotic delay induced by Eg5 inhibition (Tanenbaum et al., 2009; Vanneste et al., 2009). Nonetheless, as Eg5 inhibitors are expected to have a mitosis-specific effect and partial patient-responses have been reported, clinical trials will continue with a focus on combination therapies (Huszar et al., 2009).
Two other interesting mitotic targets, for which inhibitors are currently under investigation, are the kinases Aurora A and Polo-like kinase-1 (Lens et al., 2010). Both are overexpressed in cancer (Strebhardt and Ullrich, 2006; Lok et al., 2010) and both have important roles in G2 and mitosis (Carmena and Earnshaw, 2003; Barr et al., 2004). Inhibition of either Aurora A or Plk1 results in monopolar spindle formation, because of their roles in centrosome maturation and separation in G2 (Carmena and Earnshaw, 2003; Barr et al., 2004). As such, the most profound effects after inhibition of Plk1 or Aurora A are perturbation of mitotic progression, making both of these kinases attractive and possibly specific anti-mitotic targets (Figure 1). Many inhibitors have been produced that target these kinases, and several have already entered clinical trials (Strebhardt and Ullrich, 2006; Lok et al., 2010) (Table 1).
The kinesin motor protein, CENP-E, is the most recent addition to potential anti-mitotic targets. It is a kinetochore-associated kinesin, whose function appears to be restricted to mitosis. Upon absence or inhibition of its activity, cells are delayed in mitosis for a prolonged period of time with unaligned chromosomes (Yao et al., 2000) (Figure 1). Inhibition of CENP-E function has been shown to elicit anti-tumor effects in mouse models of spontaneous tumor formation (Weaver et al., 2007) as well as in mice bearing xenografts of human tumor cells (Wood et al., 2010). Moreover, inhibitors of CENP-E are currently being tested in phase I clinical trials (Schafer-Hales et al., 2007; Huszar et al., 2009) (Table 1).
Why does a mitotic delay result in cell death?
Cells treated with classical anti-mitotic drugs will delay mitotic progression for an extensive period of time because of the action of the mitotic checkpoint. This prolonged mitotic delay is often followed by cell death in mitosis (mitotic cell death). However, a subset of cells can escape mitotic cell death and exit (Gascoigne and Taylor, 2008). Remarkably, there is a great variation in the timing of cell death amongst cells within a genetically identical population. Thus, as a consequence of a mitotic checkpoint-dependent delay, cells either die in mitosis or they exit mitosis in a tetraploid state despite an active mitotic checkpoint, a process called mitotic checkpoint slippage (Rieder and Maiato, 2004; Brito and Rieder, 2006; Gascoigne and Taylor, 2008) (Figure 1). In several independent studies, no clear correlation was found between the duration of the mitotic delay and cell fate, indicating that the time a cell arrests in mitosis does not dictate whether a cell will die in mitosis, slip from the mitotic arrest and die in the next G1 phase or slip out and continue to proliferate (Gascoigne and Taylor, 2008; Shi et al., 2008; Brito and Rieder, 2009). However, it has become clear that during the mitotic arrest, cyclin B levels slowly drop despite an active mitotic checkpoint (Brito and Rieder, 2006). This has led to a model for drug-induced mitotic death in which two independent processes are active during the arrest (Gascoigne and Taylor, 2008). In this model, a slow, but progressive loss of cyclin B is paralleled by a slow, but steady rise in caspase activity. This predicts that once cyclin B levels have dropped below a certain threshold before caspase activation has reached its critical threshold to induce apoptosis, cells will exit mitosis without undergoing cell death in mitosis. However, when cyclin B levels have not dropped sufficiently low to exit mitosis and caspase activation has already reached its death threshold, cells will die in mitosis (Gascoigne and Taylor, 2008).
This model, however, does not provide an answer to the question on how a prolonged delay in mitosis could result in caspase activation. Mitosis is a phase in which several high-energy consuming processes are active, such as chromosome condensation, mitotic spindle formation, chromosome congression and segregation, whereas several other cellular processes, such as vesicle transport and transcription are inhibited. A prolonged mitosis could therefore easily result in energy deprivation. Moreover, the cell is extremely vulnerable during mitosis. The chromosomes are in a highly condensed state and not protected by the nuclear membrane. In fact, it has been shown that mitotic cells have an enhanced sensitivity to for example radiation treatment, (Westra and Dewey, 1971; Stobbe et al., 2002). Therefore, cells could have evolved an intrinsic pro-apoptotic pathway that is responsible for clearance of cells that spend too much time in mitosis. Indeed, recent data show that a mitotic delay of only 2 hours can already result in p53 activation, indicating that a prolonged duration of the mitotic phase can directly activate a stress response in mitotic cells (Uetake and Sluder, 2010).
Interestingly, Cyclin B-cdk1 is thought to have a central role in controlling both mitotic duration and the apoptotic machinery. It can phosphorylate and inhibit caspase 9 during mitosis (Allan and Clarke, 2007). This suggests that, during a prolonged mitosis, a slow, but steady drop in Cyclin B levels could be paralleled by a slow, but steady rise in caspase 9 activity. Recently, it has also been shown that a prolonged mitosis induces CyclinB-cdk1-dependent Mcl-1 degradation, an important anti-apoptotic protein (Harley et al., 2010). Some other reports have also suggested interplay between CyclinB-cdk1 activity and the activity of the anti-apoptotic proteins BclxL and Bcl-2 (Vantieghem et al., 2002; Terrano et al., 2010). Moreover, activity of certain mitotic kinases can inhibit or activate p53, suggesting that the cells that are delayed in mitosis are tipping the balance when it comes to p53 activation (Ando et al., 2004; Ha et al., 2007; Wu et al., 2011). Together, these findings show that a prolonged mitosis can result in both inhibition of the anti-apoptotic machinery and activation of a pro-apoptotic pathway, which provides a plausible mechanism to explain a cells’ sensitivity to a delay in mitosis.
Inhibiting mitotic exit
According to the current model for mitotic cell death, one way of pushing the balance towards tumor cell death in mitosis would be to inhibit cyclin B degradation. This way cells will not be able to slip out of mitosis and will be able to reach the threshold for apoptosis induction before mitotic exit is allowed. Indeed, inhibition of cyclin B degradation results in enhanced mitotic cell death when compared with treatment with spindle drugs (Huang et al., 2009). Moreover, inhibition of mitotic exit has led to tumor regression in a recently described conditional mouse model (Manchado et al., 2010). These findings indicate that inhibition of mitotic slippage could enhance the efficacy of the anti-mitotic drugs that were mentioned earlier in this review (Huang et al., 2009; Rieder and Medema, 2009; Zeng et al., 2010) (Table 1).
Targeting Aurora B
Targeting the cytokinetic machinery is another way of specifically disturbing mitotic cells. Cytokinesis is essential for a mitotic cell to be physically separated into two daughter cells (Barr and Gruneberg, 2007). Therefore, inhibition of cytokinesis leads to the formation of one tetraploid daughter cell containing twice as much DNA. A particularly important kinase that acts during cytokinesis is Aurora B (Kaitna et al., 2000). It has an essential role in diverse processes in mitosis (Vader et al., 2006), but the final outcome of Aurora B inhibition is the generation of a tetraploid cell. This inhibition results in efficient cell killing in a variety of tumor cell lines (Ditchfield et al., 2003; Hauf et al., 2003; Harrington et al., 2004; Kaestner et al., 2009) and does not seem to have a prominent effect on non-dividing cells, which makes it an interesting, proliferation-specific anti-cancer target (Ditchfield et al., 2003). Several Aurora B inhibitors have been generated and some have entered clinical trials (Keen and Taylor, 2009).
Promising effects of these inhibitors, some of which also target Aurora A, have been seen in mouse tumor models (Harrington et al., 2004; Wilkinson et al., 2007; Oke et al., 2009) and patients with various types of tumors (Keen and Taylor, 2009; Lok et al., 2010) (Table 1).
Advantages and disadvantages of inducing tetraploidy
Once a tetraploid cell has formed, several things can happen; the tetraploid cell can arrest or die in the following G1, or it can reduplicate its tetraploid genome and divide again (Andreassen et al., 2001; Ditchfield et al., 2003; Uetake and Sluder, 2004; Wong and Stearns, 2005; Ganem et al., 2007).
The lethality induced by Aurora B inhibition is thought to be mainly caused by the polyploidy that arises as a result of several rounds of endoreduplication and failed cell divisions (Ditchfield et al., 2003). This polyploidy can increase the burden on the cells’ metabolism, resulting in activation of stress pathways (Andreassen et al., 2001; Ganem and Pellman, 2007). Another possible cause for the observed lethality is the presence of an extra pair of centrosomes in the tetraploid cells. Centrosomes are the predominant microtubule-organizing centers of animal cells and have an important role during spindle assembly (Doxsey, 2001). Live cell imaging has shown that tetraploid cells harboring multiple centrosomes can end up with a multipolar spindle in the subsequent mitosis (Shi and King, 2005). This multipolar spindle causes many chromosomes to missegregate, generating severely aneuploid off-spring with limited cell viability (Figure 2).
Introducing tetraploid cells in both cancerous and healthy tissue could, however, have major drawbacks. Although cytokinesis failure often results in cell death, xenograft models have revealed that tetraploidy can increase the tumorigenic capacity of untransformed cells (Fujiwara et al., 2005; Mazumdar et al., 2006). Consistent with this, tetraploid cells have been found in several early malignant tissues (Galipeau et al., 1996; Olaharski et al., 2006).
A number of alternative models for the contribution of tetraploidy to the tumorigenic capacity of cells have been suggested (Ganem et al., 2007). As proposed over 100 years ago, the multipolarity often seen in tetraploid cells could, in some cases, lead to viable aneuploid progeny, which ultimately may underlie cancer formation (Boveri, 1914; Shi and King, 2005). Recently, two independent studies put forward another concept; mitotic cells harboring a multipolar spindle can, after achievement of chromosome attachments to the spindle, cluster their centrosomes. This ‘centrosome coalescence’ can convert the multipolar spindle into a bipolar spindle, but fails to resolve all of the incorrect attachments that have occurred in the multipolar spindle, resulting in frequent missegregations upon mitotic exit and, as a consequence, aneuploid daughter cells (Ganem et al., 2009; Silkworth et al., 2009) (Figure 2). Although plausible, it is unknown whether these two mechanisms actually explain the tumorigenic capacity of tetraploid cells in vivo as well.
Exploiting mitotic defects of cancer cells
Cancer cells exhibit differences in cell cycle progression when compared with normal cells. The last decennium much effort has been put in finding a way to exploit these differences to specifically target cancer cells. In the last part of this review, we will focus on two major hallmarks of tumor cells: supernumerary centrosomes and chromosomal instability (CIN) and we will discuss the various possibilities that have been proposed of exploiting these cancer-associated phenotypes.
Multiple centrosomes: achilles’ heel of tumor cells?
Supernumerary centrosomes are commonly found in tumor cells and are clearly associated with increased genetic instability and tumorigenesis (Pihan et al., 2001; Sato et al., 2001; D’Assoro et al., 2002a, 2002b; Basto et al., 2008). As mentioned above, tetraploidization is one mechanism by which cells can end up with multiple centrosomes (Meraldi et al., 2002). Other suggested mechanisms that could lead to supernumerary centrosomes are de novo centrosome formation, cell fusion or centrosome overduplication (Khodjakov et al., 2002; Nigg, 2002; Fukasawa, 2007; Uetake et al., 2007).
Tumor cells harboring multiple centrosomes often end up in an aberrant mitosis (Shi and King, 2005; Ganem et al., 2009; Silkworth et al., 2009). However, as multipolar spindles often result in cell death rather than viable aneuploid progeny (Shi and King, 2005), it is expected that tumor cells have evolved ways to suppress multipolar mitoses. Indeed, supernumerary centrosomes have been shown to cluster and form a seemingly normal bipolar spindle in various types of cells (Ring et al., 1982; Brinkley, 2001; Quintyne et al., 2005) (Figure 2).
Targeting the centrosome clustering machinery
The fact that many tumor cells can cluster their centrosomes and most likely depend on centrosome clustering to produce viable daughter cells, opens the door for anti-cancer strategies. Indeed, specific inhibition of centrosome clustering has been shown to increase the number of cells going through a multipolar mitosis, and induces enhanced cell death (Kwon et al., 2008). Using a screening-based approach, both actin-dependent forces and cell adhesion were found to be essential for bipolar spindle formation in human cells harboring multiple centrosomes. More importantly, the conserved minus-end directed motor protein HSET was identified as an essential component for cell viability specifically in cells containing supernumerary centrosomes (Kwon et al., 2008). As kinesins have been shown to be druggable targets (Mayer et al., 1999), HSET could prove to be a useful target for the treatment of cancer cells with supernumerary centrosomes (Figure 2).
Chromosomal instability: tipping the balance
CIN and cancer
In a high percentage of human tumors chromosomes frequently missegregate, causing recurrent chromosome losses and gains, a phenotype referred to as CIN. This CIN leads to aneuploid cells that contain an abnormal number of chromosomes (Lengauer et al., 1997).
Over the last decennium, extensive research has been directed at understanding the precise cause of CIN and aneuploidy in human tumors (Yuen et al., 2005; Weaver and Cleveland, 2006). Although numerous mutations in genes required for normal mitotic progression have been found, none of these mutations appear to be present in a large percentage of human tumors (Hanks et al., 2004; Wang et al., 2004; Yuen et al., 2005; Weaver and Cleveland, 2006; Barber et al., 2008; Rusan and Peifer, 2008). This suggests that it is unlikely that CIN is solely caused by mutational inactivation of genes that control chromosome segregation. In fact, gene profiling of CIN tumors demonstrated that many genes are differentially expressed in CIN cancers (Carter et al., 2006; Weaver and Cleveland, 2006). These results have led to the hypothesis that altered expression of a large variety of proteins that are involved in safeguarding the genome could provide the driving force for CIN, rather than mutational inactivation of a small set of defined CIN-suppressive genes (Yuen et al., 2005; Thompson et al., 2010). Nevertheless, a causal link does exist between CIN and cancer. Various mouse models have been generated to mimick CIN, by changing the expression of genes required for faithful mitosis (Schvartzman et al., 2010). These models have revealed the tumor-promoting capacity of CIN, but do not resolve the long-standing question whether CIN alone is sufficient to drive tumorigenesis or whether additional mutations in other genes are required as well (Duesberg et al., 2000; Baker et al., 2009; Holland and Cleveland, 2009).
The downside of being CIN
Despite our lack of understanding of the exact causes of CIN, it could nonetheless provide a useful means to specifically target tumor growth (Kops et al., 2005; Schmidt and Medema, 2006). As all CIN tumor cells repetitively lose and gain chromosomes, one might be able to increase the rate of missegregations to such a level that the majority of cell divisions will produce non-viable daughter cells. If the frequency of missegregations is sufficiently high, this will cause all cells within the tumor to eventually undergo an aberrant cell division resulting in inviable progeny, possibly serving as a selective strategy to eradicate CIN tumors (Kops et al., 2004; Janssen et al., 2009) (Figure 3). In line with such a possible negative impact of CIN on tumor cell viability, various mouse models of enhanced CIN have also revealed a possible tumor suppressive role for CIN. For example, while reducing levels of CENP-E leads to an increase in spleen and lung tumor formation, crossing these mice with p19 knockout mice or treating them with carcinogens resulted in decreased tumor formation (Weaver et al., 2007). Similar results were found in Bub1-insufficient mice; increased tumorigenesis has been observed when crossing these mice with p53 or Rb heterozygous mice, but a reduction in tumor formation in the prostate was observed when Bub1 insufficiency was combined with a reduction in PTEN (Baker et al., 2009). Importantly, this latter reduction correlated with increased cell death. These results all argue in favor of the hypothesis that the level of CIN needs to be tightly regulated in tumors: mild CIN can facilitate tumorigenesis, but severe CIN is incompatible with tumor cell viability.
Targeting the chromosome segregation machinery
If enhancement of chromosome segregation errors can specifically eradicate CIN tumor cells, then what would be the optimal targets to achieve this? Obvious candidates are proteins that ensure the fidelity of chromosome segregation. For example, inhibition of mitotic checkpoint function has been shown to cause severe chromosome segregation errors and is incompatible with human cell viability (Kops et al., 2004; Michel et al., 2004), suggesting it could represent a suitable target (Kops et al., 2005). Indeed, inhibition of the mitotic checkpoint kinase Mps1 has recently been shown to partially inhibit tumor growth in mouse models with xenografted human tumors (Colombo et al., 2010) (Table 1).
However, full mitotic checkpoint inhibition could be detrimental to normal cells as well, and this might defeat the tumor-selective basis of the approach (Michel et al., 2001). Also, it is improbable that full inhibition of checkpoint function can be achieved in clinical settings. Nonetheless, partial inhibition of mitotic checkpoint function combined with an approach that perturbs proper chromosome alignment could enhance chromosome segregation errors above the threshold required to kill tumor cells. In line with this, work from our own lab has shown that partial mitotic checkpoint inhibition in combination with sub-lethal doses of paclitaxel can produce a synergistic effect in tumor cell death that is not observed in non-transformed cells (Janssen et al., 2009) (Figure 3). Inhibition of centrosome clustering, as mentioned above, could be another approach to enhance chromosome segregation errors in CIN cells harboring multiple centrosomes (Figure 2). The multipolarity resulting from this strategy will inevitably lead to severe aneuploidy, which strongly compromises tumor cell viability (Kwon et al., 2008).
Presumably the enhanced CIN kills tumor cells because the genetic imbalance that is produced as a result of error prone chromosome segregation is too severe to produce a viable daughter cell. Obviously, segregation errors that result in loss of one or more chromosomes that contain essential genes will not produce two viable daughter cells (Torres et al., 2008). In fact, aneuploidy is in most cases incompatible with embryonic viability (Cohen, 2002). On the other hand, aneuploid tumor cells can proliferate without difficulty, which shows that the negative impact of chromosome imbalances on cell viability can be overcome.
How exactly does aneuploidy compromise cell viability? Recent work in yeast has shown that introduction of as much as a single extra chromosome leads to an extra burden on the cells’ transcription machinery, as most genes on the extra chromosome are being transcribed (Torres et al., 2007). Together with the increase in transcriptional activity, increased protein synthesis and proteasomal degradation produce a higher demand on the cellular metabolism and results in increased energy consumption (Torres et al., 2007; Williams et al., 2008).
The presence of extra chromosomes can trigger the activation of stress pathways, owing to protein imbalances, proteotoxic stress and presumably higher levels of reactive oxygen species (Torres et al., 2007; Williams et al., 2008; Li et al., 2010; Thompson and Compton, 2010). Because of activation of these stress pathways, aneuploidy will lead to a decrease in the speed of cell growth and enhanced lethality in an otherwise healthy population of cells (Torres et al., 2007; Williams et al., 2008). In line with this, it has been hypothesized that another specific strategy to kill aneuploid tumor cells could be to enhance proteotic stress, for example by inhibiting the proteasome machinery (Torres et al., 2007).
The actual molecular pathways underlying the initial cell cycle delay following single chromosome missegregations and aneuploidy are starting to emerge. Chromosome missegregation events have been shown to inhibit cell cycle progression through activation of p38 and eventually p53 (Thompson and Compton, 2010). Interestingly, inhibition of p38 function selectively targets aneuploid or tetraploid cells (Vitale et al., 2008).
Moreover, recent data suggest that ataxia telangiectasia mutated (ATM) also has a role in the observed p53 activation following acquisition of an aneuploid state (Li et al., 2010). Presumably, because of the increase in oxidative stress, ATM can get directly activated in the aneuploid cell (Guo et al., 2010) and in turn can activate p53 (Li et al., 2010). Whether other upstream pathways could contribute to the observed p53 activation is still unknown. Thus, it would seem that chromosome segregation errors and gene imbalances result in the activation of a variety of stress pathways that restrict the proliferative capacity of the newly formed aneuploid cells. The fact that aneuploid tumor cells can readily proliferate indicates that cells can adapt to this acute stress response (Torres et al., 2010). Clearly the success of a strategy that enhances chromosome imbalances in the tumor will heavily depend on the ease at which the aneuploid cell can adapt to the newly acquired genetic imbalance it is confronted with.
Specificity of exploiting CIN
The question remains on how the tumor specificity of the diverse strategies to exploit CIN can be maximized and how adverse effects on healthy dividing tissue can be minimized. Normal cells have a defined diploid content of chromosomes, whereas tumor cells mostly contain a much larger number of chromosomes. As a consequence, the time required for healthy cells to correctly align their chromosomes in mitosis is much shorter when compared with aneuploid tumor cells that typically harbor many extra chromosomes (Yang et al., 2008). Thus, decreasing the duration of mitosis by mitotic checkpoint inhibition is likely to have more disastrous effects on aneuploid tumor cells than normal diploid cells. In fact, mitotic checkpoint inhibition in healthy cells does not necessarily cause segregation errors (Buffin et al., 2007; Janssen et al., 2009) (Figure 3). Moreover, as CIN cells already start off with massive genome imbalances, they may perhaps be more sensitive to chromosome missegregation events when compared with healthy cells (Kops et al., 2005). More research is needed to determine whether CIN cells will reach the critical threshold of segregation errors more easily than healthy cells following disturbance of chromosome segregation.
Disadvantages of exploiting mitotic defects of cancer cells
Taken together, it seems plausible that preexisting mitotic defects of cancer cells can be exploited in novel anti-cancer strategies, but more research is needed to validate these therapeutic interventions. For one, it remains largely unknown what the long-term effect of inhibition of the centrosome clustering machinery is on normal dividing cells (Godinho et al., 2009). What's more, because of the random clustering of centrosomes, cells with supernumerary centrosomes will frequently give rise to daughter cells that inherit only a single centrosome. Thus, within a population of tumor cells with supernumerary centrosomes, a subset of cells will exist or arise that contains the right number of centrosomes. This means that a fraction of the tumor cells within the population will not be sensitive to this strategy and can drive a relapse (Figure 2). Whether this will be a serious limitation of this approach will depend on the frequency at which these ‘normal’ daughter cells acquire extra centrosomes.
Increasing the amount of CIN will also inevitably lead to adverse side effects when used as an anti-cancer therapy. For example, introduction of chromosome missegregations will affect the viability of normal diploid cells as well (Thompson and Compton, 2010). Moreover, as mentioned above, CIN has been implicated in promoting tumorigenesis and therefore, exploiting CIN could produce secondary tumors in the long term by inducing chromosomal rearrangements that provide a growth advantage for the aneuploid cells over their diploid counterparts (Figure 3). However, it has also been shown that aneuploidy inducing treatments have a negative impact on cell cycle progression and viability in an otherwise healthy population of cells (Figure 3). This leads to selection for cells with a diploid karyotype (Thompson and Compton, 2008, 2010; Janssen et al., 2009). Moreover, it has been shown that aneuploid cells need to acquire additional (genetic) defects to overcome the decrease in cell growth (Torres et al., 2010). Together, these mechanisms decrease the probability of ‘healthy’ aneuploid cells to become tumorigenic.
Whether inhibition of mitosis-specific proteins or exploiting supernumerary centrosomes and CIN could sort any clinical efficacy remains to be tested in xenografts and tumor-prone mouse models. All in all, exploiting cancer-specific phenotypes deserves further attention as these could lead to new therapeutic interventions, which are possibly less harmful for healthy dividing tissues.
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The authors declare no conflict of interest.
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Janssen, A., Medema, R. Mitosis as an anti-cancer target. Oncogene 30, 2799–2809 (2011). https://doi.org/10.1038/onc.2011.30
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